1. Field of the Invention
This invention relates to silyl ether prodrugs containing at least one hydrophilic group on the silicon atom. The prodrugs hydrolyze at low pH, enabling release of the active drug in the gastric pH range. The invention further relates to a method of preparation of the silyl ether prodrugs, and to a method of treatment or prevention of gastric ulcers with a prodrug of misoprostol.
2. Related Background Art
It is known in the art that trialkylsilyl ether groups can be employed in pH-selective delivery systems for drug molecules. J. Chem. Soc. Perkin Trans., Vol. 10, p. 3043 (1992); J. Pharm. Sci., Vol. 77, p. 116 (1988); Int. J. Pharm., Vol. 28, p. 1 (1986); J. Pharm. Sci., Vol. 71, p. 1 (1982); Scientia Pharmaceutica, Vol. 43, p. 217 (1975); and JP 8,165,301. In these references, prodrugs containing trialkylsilyl ethers were formed from hydroxyl-containing drugs and found to undergo hydrolysis to release the drug only at low pH values. Such systems are of particular interest for selective delivery of drugs to the stomach, where pH values are typically in the range from 1 to 4. When any remaining prodrug passes into the intestine, where pH values are typically about 7, release of the drug ceases, thus avoiding the side effects usually associated with intestinal absorption.
Trialkylsilyl ethers formed at one or more of the hydroxyl groups of drugs in the prostaglandin series are also well known. In U.S. Pat. No. 3,965,143, a triethylsilyl ether is formed at position 16 of misoprostol, a prostaglandin drug. In U.S. Pat. Nos. 5,055,604 and 5,075,478, and in ES 545634, the 11-triethylsilyl ether of misoprostol is formed. U.S. Pat. No. 5,252,763 discloses a process for making a trialkylsilyl ether, in which the alkyl groups contain from 1 to 6 carbon atoms, at the 11 position of misoprostol. Finally, PCT Application No. WO 96/28419 discloses a trialkylsilyl ether at the 11 position, in which the alkyl groups contain from 1 to 8 carbon atoms. In all of the aforementioned references, the trialkylsilyl ethers are disclosed only as intermediates in the synthesis of prostaglandins. No suggestion is made that these compounds would be useful as delivery systems for prostaglandins, or that hydrophilic groups be substituted for the alkyl groups in the trialkylsilyl ether.
A polymeric delivery system in which a drug, such as a prostaglandin, is covalently bonded through a hydroxyl substituent, and is selectively released at a predetermined pH is described in PCT Application No. WO 92/01477; U.S. Pat. No. 5,474,767; and Journal of Medicinal Chemistry, Vol. 36, p. 3087 (1993). The pH-selective drug delivery systems described in these references comprise a drug covalently bonded to a linker by reaction with a silyl chloride functional group on the linker, thus forming an acid-sensitive silyl ether bond, and a polymer which is covalently bonded to the linker-drug combination. The polymer is crosslinked following bonding of the linker, or in some cases, prior to bonding of the linker. In an acidic environment, the silyl ether bonds hydrolyze, allowing the drug molecules to diffuse from the polymer matrix. However, unlike many prodrugs, the polymer-bound drug has no significant hydrophilic nature. No suggestion is made in these references to attach a hydrophilic group to the drug.
This invention provides a compound of the formula
AWxe2x80x94SiR1R2R3
wherein R1 and R2 are independently alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, or a hydrophilic group; R3 is a hydrophilic group; and AW is the covalently bonded form of a drug AWH, wherein W is O, CO2, NH, S, or an enolate group. Of course, each of R1, R2 or R3 or all may independently contain hydrophilic groups. The hydrophilic group may be non-neutral, or may be a polyol. In a most preferred embodiment the hydrophilic group is a tertiary amine or polyethylene glycol. This compound serves as a prodrug for the drug AWH.
This invention also provides a method for preparing these compounds by first reacting the drug AWH with a compound of formula
YSiR1R2R7
wherein Y is halo, or an alkyl-, haloalkyl-, aryl-, alkaryl-, aralkyl-, or haloaryl- sulfonate ester; R1 and R2 are as previously described; R7 is a group substituted by a halo group. The product of this first step is reacted with either (1) a compound containing at least one amino group or (2) a polyol. In a preferred embodiment, the product of the first step is reacted with a compound containing at least one tertiary amine. In another preferred embodiment, the product of the first step is reacted with an amine-substituted polyol, or an alkylamine of twenty carbons or less which can then be further reacted with a transformed polyol to provide an amine-substituted polyol. In another preferred embodiment, the product of the first step can be reacted with an unmodified polyol which may optionally be transformed and then reacted with a tertiary amine. In a preferred embodiment, the polyols of this invention are polyethylene glycol (PEG).
This invention also provides a method of treatment or prevention of gastric ulcers by administering the prodrug compounds of this invention.
The following terms used herein are defined. The term xe2x80x9cTHFxe2x80x9d indicates the solvent tetrahydrofuran. The term xe2x80x9cDMFxe2x80x9d indicates the solvent N,N-dimethylformamide. The term xe2x80x9cmercaptoxe2x80x9d refers to the substituent moiety SH, bonded through its sulfur atom to a carbon atom on a substrate. The term xe2x80x9calkylxe2x80x9d refers to a straight or branched alkyl group containing from 1 to 20 carbon atoms. The term xe2x80x9calkenylxe2x80x9d refers to a straight or branched hydrocarbon group containing from 1 to 20 carbon atoms and at least one carbon-carbon double bond. The term xe2x80x9calkynylxe2x80x9d refers to a straight or branched hydrocarbon group containing from 1 to 20 carbon atoms and at least one carbon-carbon triple bond. The term xe2x80x9ccycloalkylxe2x80x9d refers to a cyclic alkyl group containing up to 20 carbon atoms. The term xe2x80x9carylxe2x80x9d refers to a substituent derived from a cyclic aromatic compound having up to 20 carbon atoms. The term xe2x80x9caralkylxe2x80x9d refers to an alkyl group substituted by an aryl group. The term xe2x80x9calkarylxe2x80x9d refers to an aryl group substituted by an alkyl group. The term xe2x80x9chaloxe2x80x9d means a fluoro, chloro, bromo, or iodo group. The term xe2x80x9cPhxe2x80x9d refers to a difunctional phenylene moiety substituted at the 1 and 4 positions. The term xe2x80x9cpolyolxe2x80x9d refers to polyhydroxyl-containing compounds, containing 2 or more hydroxyl moieties, preferably on a carbon backbone which may be substituted by oxygen. Exemplary polyol compounds include, but are not limited to, glycols, e.g., ethylene glycol, propylene glycol; polyglycols, e.g.,PEG, polypropylene glycol; and polyhydric alcohols.
The term xe2x80x9ctransformxe2x80x9d refers to the reaction by which a hydroxyl group on a polyol has been substituted with a leaving group, and the term xe2x80x9ctransformed polyolxe2x80x9d refers to a polyol which has been thus reacted. Polyols may be transformed by reaction with tosylate, mesylate, triflate or other methods well-known in the art. The term xe2x80x9cunmodified polyolxe2x80x9d refers to a polyol which has not been transformed.
The prodrug compounds of this invention have the general formula
AWxe2x80x94SiR1R2R3
wherein R1 and R2 are independently alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, or a hydrophilic group; R3 is a hydrophilic group; and AW is the covalently bonded form of a drug AWH, wherein W is O, CO2, NH, S or an enolate group. Each of R1, R2 or R3 or all may independently contain hydrophilic groups. The hydrophilic group may be non-neutral, or may be a polyol. The AW-Si bond in these molecules is susceptible to hydrolysis at low pH values. Hydrolysis of the AW-Si bond releases the drug AWH from the prodrug when the prodrug reaches the low-pH environment of the stomach. Conversely, any remaining prodrug which passes into the higher-pH environment of the intestines will no longer release the drug, thereby avoiding the side effects usually associated with intestinal release.
Preferably, R1 and R2 are independently alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, or polyol, and R3 is a group comprising at least one quaternary ammonium salt or a polyethylene glycol, making R3 a hydrophilic group that is non-neutral or a polyol.
If R3 contains two, three, or four amino groups or quaternary ammonium salt groups, the prodrug may contain two, three, or four AWSiR1R2 groups, respectively. Moreover, more than one type of drug AW may be released from this multiple prodrug system. Typically, R3 will be a group with the formula
xe2x80x83xe2x80x94Lxe2x80x94(NR4R5R6)+Xxe2x88x92
wherein Xxe2x88x92 is a halide ion or any pharmaceutically acceptable anion; L is a difunctional alkyl, alkenyl, or alkynyl group, a polyol, or a group with the formula
(CH2)mxe2x80x94Arxe2x80x94(CH2)n
wherein Ar is a difunctional aryl or cycloalkyl group, m is an integer from 0 to 3 inclusive, and n is an integer from 0 to 2 inclusive; R4 and R5 are independently alkyl, alkenyl, alkynyl or polyol; and R6 is alkyl, alkenyl, alkynyl, polyol, or a group with the formula
xe2x80x94Bxe2x80x94(NR4R5)+xe2x80x94Lxe2x80x94SiR1R2WA Xxe2x88x92
wherein B is a difunctional alkyl, alkenyl, alkynyl group, a polyol, or a group with the formula
(CH2)jxe2x80x94Arxe2x80x94(CH2)k
wherein j is an integer from 0 to 3 inclusive, and k is an integer from 0 to 3 inclusive.
The compound of this invention will be a dimer if, in the aforementioned definition of R3, the choice for R6 is a group with the formula
xe2x80x94Bxe2x80x94(NR4R5)+xe2x80x94Lxe2x80x94SiR1R2WA Xxe2x88x92
With this choice for R6, the resulting dimeric structure of the compound will be
AWSiR1R2xe2x80x94Lxe2x80x94(NR4R5)+xe2x80x94Bxe2x80x94(NR4R5)+xe2x80x94Lxe2x80x94SiR1R2WA 2Xxe2x88x92
As previously noted, in an alternative embodiment, AW may be more than one type of drug.
Most preferably, R1 and R2 are independently alkyl or aryl, and R3 is a group of the formula 
This represents the choice of L as a group with the formula
(CH2)mxe2x80x94Arxe2x80x94(CH2)n
wherein Ar is a 1,4-phenylene group, m is 2, n is 1; R4, R5 and R6 are all methyl; and Xxe2x88x92 is Clxe2x88x92.
Hydroxyl-containing drugs, i.e. AOH, are most preferred for incorporation into the compound of this invention, especially those wherein gastric release, at a typical gastric pH value between 1 and 4, is preferred over intestinal release, or wherein control of the rate of release is desired for systemic action. For example, drugs for which delivery to the stomach is preferred include natural or synthetic prostaglandins and prostacyclins (e.g., misoprostol, enisoprost, enprostil, iloprost, and arbaprostil), any drugs for treatment or prevention of peptic ulcers, gastric antisecretory drugs, antimicrobial drugs, prokinetic drugs, cytoprotective drugs and the like. Exemplary antimicrobial drugs include tetracycline, metronidazole and erythromycin which can be used for the eradication of gastric microbes. The most preferred drug for use in the prodrug of this invention is misoprostol.
This invention also includes a method for making the prodrug by first reacting the drug AWH with a compound of formula
YSiR1R2R7
wherein Y is halo, or an alkyl-, haloalkyl-, aryl-, alkaryl-, aralkyl-, or haloaryl- sulfonate ester; R1 and R2 are as previously described; R7 is a group substituted by a halo group. The product of this first step is reacted with either (1) a compound containing at least one amino group or (2) a polyol. In a preferred embodiment, the product of the first step is reacted with a compound containing at least one tertiary amine. In another preferred embodiment, the product of the first step is reacted with an amine-substituted polyol, or an alkylamine of twenty carbons or less which can then be further reacted with a transformed polyol to provide an amine-substituted polyol. In another preferred embodiment, the product of the first step can be reacted with a polyol which may optionally be transformed and then reacted with a tertiary amine. In a preferred embodiment, the polyols of this invention are polyethylene glycol (PEG).
In a preferred embodiment of this invention, a drug AWH is first reacted with a compound of the formula
YSiR1R2R7
wherein R7 is a group of the formula xe2x80x94Lxe2x80x94X, or a group of the formula
xe2x80x83xe2x80x94(CH2)mxe2x80x94Arxe2x80x94(CH2)nX
to form a compound of formula AWSiR1R2R7, wherein Y, R1, R2, and L are as previously described and X is halo. This first step couples the drug with a substituted silane to form a silyl ether, silyl ester, silyl amide, silyl thioether, or silyl enol ether.
In a second step, the silyl ether product of the first step is then reacted with either (1) a compound containing at least one amino group or (2) a polyol.
In a preferred embodiment of the second step, the compound containing at least one amino group is represented by the formula Z(NR4R5)p, wherein R4 and R5 are independently hydrogen, alkyl, alkenyl, alkynyl or polyol; Z is hydrogen, alkyl, alkenyl, alkynyl or polyol, and p is 1; or p is 2 and Z is a difunctional alkyl, alkenyl, or alkynyl group, a polyol, or a group with the formula
(CH2)jxe2x80x94Arxe2x80x94(CH2)k
wherein j is an integer from 0 to 3 inclusive, and k is an integer from 0 to 3 inclusive. In this step, a halo substituent on one of the silyl substituents is displaced by an amino group. In a preferred embodiment, R4 and R5 are independently alkyl, alkenyl or alkynyl; Z is alkyl, alkenyl or alkynyl, and the halo substituent on one of the silyl substituents is displaced by a tertiary amine to produce a quaternary ammonium salt. The product of these transformations will be a dimer if p is 2 and Z is difunctional, i.e. if Z(NR4R5)p is a diamine. In such a case, the diamine will preferably displace a halo or sulfonate substituent from each of two molecules of the silyl starting material, thereby producing a symmetrical dimeric structure.
If the anion, Xxe2x88x92, produced by reaction of R7 with an amino group, is not a pharmaceutically acceptable anion, any of the ion exchange methods well known in the art may be employed to replace the anion with one that is pharmaceutically acceptable.
In another preferred embodiment of the second step, the silyl ether product of the first step is reacted with an amine-substituted polyol containing at least one amino group. Preferably, the polyol is an amino or diamino polyethylene glycol represented by the formula R8(CH2CH2Oxe2x80x94CH2CH2)kNH2 wherein R8 is an alkoxy, amino, hydroxyl or hydrogen group, and k is an integer in the range of 1-100, preferably 10-50. Amino or diamino polyethylene glycols are commercially available from Sigma-Aldrich Corp in St. Louis, Mo. or from Shearwater Polymers Inc. in Huntsville, Ala. The resulting amino-substituted polyol system will be polar as a result of the hydroxyl groups on the polyol, thus providing a useful hydrophilic character for pharmaceutical application.
This resulting amine-substituted polyol system can also be achieved by another route. Instead of reacting the silyl ether product of the first step with an amine-substituted polyol, the product is reacted with an alkylamine of twenty carbons or less. The alkylamine is then reacted with a transformed polyol to provide the same resulting amine-substituted polyol system described above. This alternate route may be commercially advantageous since unsubstituted polyol reagents are less expensive than amine-substituted polyols.
In yet another preferred embodiment, the silyl ether product of the first step can instead be reacted with a polyol, represented by the formula R8(CH2CH2Oxe2x80x94CH2CH2)R9, wherein R8 is as described above, R9 is an alkoxy, amino or hydroxyl group, and k is as described above. While the resulting polyol system may be non-neutral, it is nonetheless polar and has useful hydrophilic character for pharmaceutical application. As an optional step, the resulting polyol system can be further modified by transforming a hydroxyl group on the polyol into a leaving group, and reacting the transformed polyol with a tertiary amine of the formula Z(NR4R5)p, wherein Z, N, R4, R5 and p are described as above.
A preferred silyl chloride reactant for use in the method of this invention may be synthesized in a two-step process. The first step is introduction of a silyl moiety into an unsaturated substituent on a substrate which also bears a reactive halo substituent. This is preferably accomplished by catalytic hydrosilylation. Suitable substrates for this reaction include those having a carbon-carbon double bond which can undergo the hydrosilylation reaction, as well as a reactive halo substituent, such as the 4-vinylbenzyl halides. The most preferred substrate is 4-vinylbenzyl chloride. Preferred silanes for use in this reaction include the dialkylsilanes or alkylarylsilanes, such as dimethylsilane, methylethylsilane, diethylsilane, methylisopropylsilane, ethylisopropylsilane, diisopropylsilane, isobutylisopropylsilane, isobutylpropylsilane, isobutylethylsilane, isobutylmethylsilane, propylisopropylsilane, propylethylsilane, propylisobutylsilane, tert-butylmethylsilane, tert-butylethylsilane, tert-butylphenylsilane, tert-butylisopropylsilane, tert-butylisobutylsilane, and the like. The most preferred silanes are diisopropylsilane, tert-butylmethylsilane, and tert-butylphenylsilane. Preferred catalysts for promoting the hydrosilylation reaction include a variety of platinum and rhodium catalysts, such as platinum divinyltetramethyldisiloxane and tris(triphenylphosphine)rhodium(I) chloride (xe2x80x9cWilkinson""s catalystxe2x80x9d). The most preferred catalyst is platinum divinyltetramethyldisiloxane. Preferred solvents for use in hydrosilylation may include any solvent which will dissolve the substrate and which will not undergo hydrosilylation. Examples are the aromatic hydrocarbon solvents such as toluene, any of the xylenes, and ethylbenzene, and aliphatic hydrocarbon solvents such as any of the pentanes, hexanes, heptanes, octanes, cyclohexane, cyclopentane, and the like, and mixtures thereof. The most preferred solvents are toluene and the xylenes, and mixtures thereof. The hydrosilylation reaction is preferably carried out at a temperature in the range from about 15xc2x0 C. to about 120xc2x0 C., most preferably from 50xc2x0 C. to 80xc2x0 C. Preferably, the reaction is allowed to proceed for a period of about 1 to about 24 hours, most preferably from 5 to 14 hours.
The second step in preparation of a preferred silyl chloride starting material is chlorination of the silane product of the first step. This is typically accomplished by treatment with a solution of chlorine gas in an organic solvent. Suitable solvents for this reaction include the halogenated solvents, such as chlorobenzene, 1,2-dichlorobenzene, dichloromethane, tetrachloromethane, chloroform, 1,2-dichloroethane, 1,1,1-trichloroethane, 1,1,2,2-tetrachloroethane, tetrachloroethylene, and the like. Preferred solvents are dichloromethane, 1,2-dichloroethane, and tetrachloromethane. The most preferred solvent is dichloromethane. The chlorination is typically carried out below room temperature, preferably below about xe2x88x9220xc2x0 C., most preferably at about xe2x88x9278xc2x0 C. Preferably, the reaction is allowed to proceed for a period of about 10 minutes to about 3 hours. The reaction mixture may be monitored using an analytical method capable of detecting the level of starting material, product, or both, such as gas chromatography. The reaction may be allowed to proceed until the starting material is substantially consumed.
The steps of hydrosilylation and chlorination in this preferred embodiment may effectively be combined by carrying out the hydrosilylation under the same conditions, but with a dialkylchlorosilane or alkylarylchlorosilane starting material rather than a dialkylsilane or alkylarylsilane starting material. For example, hydrosilylation of 4-vinylbenzyl chloride with a dialkylchlorosilane produces the desired 1-dialkylchlorosilyl-2-[4-(chloromethyl)phenyl]ethane directly.
In a preferred embodiment of this invention, the preferred silyl chloride starting material is coupled to the drug molecule. This is typically accomplished by combining the drug and the silyl chloride in a solvent. Suitable solvents for this step include those capable of dissolving the drug, but which are not reactive towards the silyl chloride functional group, including the polar aprotic solvents, such as N,N-dimethylformamide (DMF), THF, N,N-dimethylacetamide, N-methylpyrrolidone, 1,2-dimethoxyethane, and halogenated solvents such as chlorobenzene, 1,2-dichlorobenzene, dichloromethane, tetrachloromethane, chloroform, 1,2-dichloroethane, 1,1,1-trichloroethane, 1,1,2,2-tetrachloroethane, tetrachloroethylene, and the like. Preferred solvents are DMF, dichloromethane, and THF. The most preferred solvent is DMF. An additional compound may be added as a promoter for the coupling reaction, typically a nitrogen-containing compound.
Preferred promoters include imidazole and 4-dimethylaminopyridine. The most preferred promoter is imidazole. This reaction is preferably carried out at a temperature in the range from about 15xc2x0 C. to about 100xc2x0 C., most preferably from 20xc2x0 C. to 40xc2x0 C. Preferably, the reaction is allowed to proceed for a period of about 1 to about 18 hours. The progress of the reaction may be followed by using a method capable of detecting the level of starting material, product, or both, such as thin-layer chromatography or liquid chromatography. The reaction may be allowed to proceed until the starting material is substantially consumed.
Preferably, the coupled product described above is then reacted with any one of the following (1) a tertiary amine, (2) an amine-substituted polyol, (3) an alkylamine followed by a transformed polyol, or (4) an unmodified polyol, which may optionally be transformed and then reacted with a tertiary amine. Any of these four reactions is typically accomplished by combining the coupled product and the amine or polyol in a solvent. Suitable solvents for this step include the polar aprotic solvents such as THF, DMF, N,N-dimethylacetamide, N-methylpyrrolidone, 1,2-dimethoxyethane, and the like. The preferred solvents are DMF and THF. The most preferred solvent is THF. Preferably, this reaction is carried out at a temperature in the range from about 15xc2x0 C. to about 75xc2x0 C., most preferably from 20xc2x0 C. to 40xc2x0 C. Preferably, the reaction is allowed to proceed for a period of about 10 hours to about 3 days, most preferably from 18 hours to 2 days.
If the coupled product is reacted with compounds containing a polyol, then a catalyst may be added to the solvent. Recommended catalysts include, but are not limited to, potassium iodide, sodium iodide and tetrabutyl ammonium. Preferably, the catalyst should be added under temperature conditions that range from room temperature to 100xc2x0 C.
If transformation of the polyol is required, one of the hydroxyl groups on the unmodified polyol may be transformed into a leaving group by reaction with tosylate, mesylate or triflate or by other methods well known in the art. The reaction is accomplished under temperature conditions that range from room temperature to 100xc2x0 C. The transformed polyol can then be reacted with an amino group of an alkylamine or a tertiary amine as described above.
Reaction of the coupled drug product to polyols or their derivatives results in a drug delivery system with a substantially slower release rate. The release rate can be further controlled by the size of the polyol, with larger molecular weight polyols resulting in faster release rates. Biocompatible polyols such as PEGs offer other advantages in that they are soluble in both aqueous and organic solvents and are non-toxic, non-immunogenic and readily excreted. PEGs are commercially available in various molecular weights from such sources as Sigma-Aldrich Corp in St. Louis, Mo. or from Shearwater Polymers Inc. in Huntsville, Ala.
Another embodiment of this invention is directed to the method of treating or preventing gastric ulcers by administration of the prodrug of this invention. The active ingredient in this invention may be any substance that is desired for administration by selective release in an acidic environment, such as a drug, a sequestrant, or a ligand for complexation of metals. In each case, a suitable active ingredient will be one which forms a pH-sensitive covalent bond with a silyl compound. The active ingredient is substituted by a hydroxyl, carboxylate, amino, mercapto, or enolizable carbonyl group which is capable of reacting with a silyl compound to form a covalent bond. Preferably, the active ingredient is a hydroxy-containing biologically active material, e.g., a drug, intended to be administered orally, especially those wherein gastric release, at a typical gastric pH value between 1 and 6, is preferred over intestinal release, or wherein control of the rate of release is desired for systemic action. For example, drugs for which delivery to the stomach is preferred include natural or synthetic prostaglandins and prostacyclins (e.g., misoprostol, enisoprost, enprostil, iloprost, and arbaprostil), any other drugs for treatment or prevention of peptic ulcers, gastric antisecretory drugs, antimicrobial drugs, prokinetic drugs, cytoprotective drugs and the like. Preferred prostaglandin drugs which may be delivered by the prodrug of this invention are those described in PCT Application No. WO 92/01477, the disclosure of which is incorporated by reference herein. Exemplary antimicrobial drugs include tetracycline, metronidazole and erythromycin which can be used for the eradication of gastric microbes. The most preferred drug for delivery by the prodrug of this invention is misoprostol.
The preferred amount of prodrug to be administered is an amount that is sufficient to prevent, cure, or treat a condition for a desired period of time for which the delivery system of this invention is to be administered, and such an amount is referred to herein as xe2x80x9can effective amountxe2x80x9d. As is well known, particularly in the medicinal arts, effective amounts of medicinal agents vary with the particular agent employed, the condition being treated and the rate at which the composition containing the medicinal agent is eliminated from the body, as well as varying with the subject in which it is used, and the body weight of that subject. An effective amount is that amount which in a composition of this invention provides a sufficient amount of the active ingredient to provide the requisite activity of the active ingredient in the body of the treated subject for the desired period of time, and can be less than that amount usually used.
Inasmuch as amounts of particular active ingredients that are suitable for treating particular conditions are generally known, it is relatively easy to formulate a series of prodrugs containing a range of such active ingredients to determine the effective amount of such an active ingredient for a particular prodrug. Based upon a reading of the description herein and of the following examples, it is within the skill of the art to select an amount of any particular active ingredient and to form a prodrug as herein described for delivering an effective amount of such an active ingredient without undue experimentation. While the effective amount for all active ingredients cannot be stated, typical compositions of this invention may contain about one microgram to about one gram of active ingredient per dose administered. More preferably, a composition of this invention may contain about 1 microgram to about 250 milligrams per dose.